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1149 KiB

Open AccessArticle

Activation of LTRs from Different Human Endogenous Retrovirus (HERV) Families by the HTLV-1 Tax Protein and T-Cell Activators

by Chirine Toufaily, Sebastien Landry, Christine Leib-Mosch, Eric Rassart and Benoit Barbeau

Viruses 2011, 3(11), 2146-2159; https://doi.org/10.3390/v3112146 - 2 Nov 2011

Cited by 52 | Viewed by 7413

Abstract

Human endogenous retroviruses (HERVs) represent approximately 8% of our genome. HERVs influence cellular gene expression and contribute to normal physiological processes such as cellular differentiation and morphogenesis. HERVs have also been associated with certain pathological conditions, including cancer and neurodegenerative diseases. As HTLV-1 [...] Read more.

Human endogenous retroviruses (HERVs) represent approximately 8% of our genome. HERVs influence cellular gene expression and contribute to normal physiological processes such as cellular differentiation and morphogenesis. HERVs have also been associated with certain pathological conditions, including cancer and neurodegenerative diseases. As HTLV-1 causes adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and has been shown to modulate host gene expression mainly through the expression of the powerful Tax transactivator, herein we were interested in looking at the potential modulation capacity of HTLV-1 Tax on HERV expression. In order to evaluate the promoter activity of different HERV LTRs, pHERV-LTR-luc constructs were co-transfected in Jurkat T-cells with a Tax expression vector. Tax expression potently increased the LTR activity of HERV-W8 and HERV-H (MC16). In parallel, Jurkat cells were also stimulated with different T-cell-activating agents and HERV LTRs were observed to respond to different combination of Forskolin, bpV[pic] a protein tyrosine phosphatase inhibitor, and PMA. Transfection of expression vectors for different Tax mutants in Jurkat cells showed that several transcription factors including CREB appeared to be important for HERV-W8 LTR activation. Deletion mutants were derived from the HERV-W8 LTR and the region from −137 to −123 was found to be important for LTR response following Tax expression in Jurkat cells, while a different region was shown to be required in cells treated with activators. Our results thus demonstrated that HTLV-1 Tax activates several HERV LTRs. This raises the possibility that upregulated HERV expression could be involved in diseases associated with HTLV-1 infection. Full article

(This article belongs to the Special Issue Recent Developments in HTLV Research)

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1431 KiB

Open AccessArticle

Inhibition of Geranylgeranyl Transferase-I Decreases Cell Viability of HTLV-1-Transformed Cells

by Dustin C. Edwards, Katherine M. McKinnon, Claudio Fenizia, Kyung-Jin Jung, John N. Brady and Cynthia A. Pise-Masison

Viruses 2011, 3(10), 1815-1835; https://doi.org/10.3390/v3101815 - 10 Oct 2011

Cited by 4 | Viewed by 4887

Abstract

Human T-cell leukemia virus type-1 (HTLV-1) is the etiological agent of adult T-cell leukemia (ATL), an aggressive and highly chemoresistant malignancy. Rho family GTPases regulate multiple signaling pathways in tumorigenesis: cytoskeletal organization, transcription, cell cycle progression, and cell proliferation. Geranylgeranylation of Rho family [...] Read more.

Human T-cell leukemia virus type-1 (HTLV-1) is the etiological agent of adult T-cell leukemia (ATL), an aggressive and highly chemoresistant malignancy. Rho family GTPases regulate multiple signaling pathways in tumorigenesis: cytoskeletal organization, transcription, cell cycle progression, and cell proliferation. Geranylgeranylation of Rho family GTPases is essential for cell membrane localization and activation of these proteins. It is currently unknown whether HTLV-1-transformed cells are preferentially sensitive to geranylgeranylation inhibitors, such as GGTI-298. In this report, we demonstrate that GGTI-298 decreased cell viability and induced G₂/M phase accumulation of HTLV-1-transformed cells, independent of p53 reactivation. HTLV-1-LTR transcriptional activity was inhibited and Tax protein levels decreased following treatment with GGTI-298. Furthermore, GGTI-298 decreased activation of NF-κB, a downstream target of Rho family GTPases. These studies suggest that protein geranylgeranylation contributes to dysregulation of cell survival pathways in HTLV-1-transformed cells. Full article

(This article belongs to the Special Issue Recent Developments in HTLV Research)

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437 KiB

Open AccessArticle

Direct Inhibition of RNAse T2 Expression by the HTLV-1 Viral Protein Tax

by Nicholas Polakowski, Hongjin Han and Isabelle Lemasson

Viruses 2011, 3(8), 1485-1500; https://doi.org/10.3390/v3081485 - 18 Aug 2011

Cited by 8 | Viewed by 5148

Abstract

Adult T-cell leukemia (ATL) is one of the primary diseases caused by Human T-cell Leukemia Virus type 1 (HTLV-1) infection. The virally-encoded Tax protein is believed to initiate early events in the development of this disease, as it is able to promote immortalization [...] Read more.

Adult T-cell leukemia (ATL) is one of the primary diseases caused by Human T-cell Leukemia Virus type 1 (HTLV-1) infection. The virally-encoded Tax protein is believed to initiate early events in the development of this disease, as it is able to promote immortalization of T-cells and transformation of other cell types. These processes may be aided by the ability of the viral protein to directly deregulate expression of specific cellular genes through interactions with numerous transcriptional regulators. To identify gene promoters where Tax is localized, we isolated Tax-DNA complexes from an HTLV-1-infected T-cell line through a chromatin immunoprecipitation (ChIP) assay and used the DNA to probe a CpG island microarray. A site within the RNASET2 gene was found to be occupied by Tax. Real-time PCR analysis confirmed this result, and transient expression of Tax in uninfected cells led to the recruitment of the viral protein to the promoter. This event correlated with a decrease in the level of RNase T2 mRNA and protein, suggesting that Tax represses expression of this gene. Loss of RNase T2 expression occurs in certain hematological malignancies and other forms of cancer, and RNase T2 was recently reported to function as a tumor suppressor. Consequently, a reduction in the level of RNase T2 by Tax may play a role in ATL development. Full article

(This article belongs to the Special Issue Recent Developments in HTLV Research)

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Open AccessArticle

C7a, a Biphosphinic Cyclopalladated Compound, Efficiently Controls the Development of a Patient-Derived Xenograft Model of Adult T Cell Leukemia/Lymphoma

by Ana B. Guimaraes-Correa, Lindsey B. Crawford, Carlos R. Figueiredo, Karina P. Gimenes, Lorena A. Pinto, Maria Fernanda Rios Grassi, Gerold Feuer, Luiz R. Travassos, Antonio C.F. Caires, Elaine G. Rodrigues and Susan J. Marriott

Viruses 2011, 3(7), 1041-1058; https://doi.org/10.3390/v3071041 - 5 Jul 2011

Cited by 18 | Viewed by 7003

Abstract

Adult T-cell leukemia/lymphoma (ATLL) is a highly aggressive disease that occurs in individuals infected with the human T lymphotropic virus type 1 (HTLV-1). Patients with aggressive ATLL have a poor prognosis because the leukemic cells are resistant to conventional chemotherapy. We have investigated [...] Read more.

Adult T-cell leukemia/lymphoma (ATLL) is a highly aggressive disease that occurs in individuals infected with the human T lymphotropic virus type 1 (HTLV-1). Patients with aggressive ATLL have a poor prognosis because the leukemic cells are resistant to conventional chemotherapy. We have investigated the therapeutic efficacy of a biphosphinic cyclopalladated complex {Pd₂ [S₍₋₎C², N-dmpa]₂ (μ-dppe)Cl₂}, termed C7a, in a patient-derived xenograft model of ATLL, and investigated the mechanism of C7a action in HTLV-1-positive and negative transformed T cell lines in vitro. In vivo survival studies in immunocompromised mice inoculated with human RV-ATL cells and intraperitoneally treated with C7a led to significantly increased survival of the treated mice. We investigated the mechanism of C7a activity in vitro and found that it induced mitochondrial release of cytochrome c, caspase activation, nuclear condensation and DNA degradation. These results suggest that C7a triggers apoptotic cell death in both HTLV-1 infected and uninfected human transformed T-cell lines. Significantly, C7a was not cytotoxic to peripheral blood mononuclear cells (PBMC) from healthy donors and HTLV-1-infected individuals. C7a inhibited more than 60% of the ex vivo spontaneous proliferation of PBMC from HTLV-1-infected individuals. These results support a potential therapeutic role for C7a in both ATLL and HTLV-1-negative T-cell lymphomas. Full article

(This article belongs to the Special Issue Recent Developments in HTLV Research)

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Graphical abstract

308 KiB

Open AccessArticle

Susceptibility of Primary HTLV-1 Isolates from Patients with HTLV-1-Associated Myelopathy to Reverse Transcriptase Inhibitors

by Beatrice Macchi, Emanuela Balestrieri, Arianna Ascolani, Silva Hilburn, Fabiola Martin, Antonio Mastino and Graham P Taylor

Viruses 2011, 3(5), 469-483; https://doi.org/10.3390/v3050469 - 5 May 2011

Cited by 38 | Viewed by 8357

Abstract

Since human T-lymphotropic virus type 1 (HTLV-1)-associated diseases are associated with a high HTLV-1 load, reducing this load may treat or prevent disease. However, despite in vitro evidence that certain nucleoside/nucleotide analogue reverse transcriptase inhibitors (NRTIs) are active against HTLV-1, in vivo results [...] Read more.

Since human T-lymphotropic virus type 1 (HTLV-1)-associated diseases are associated with a high HTLV-1 load, reducing this load may treat or prevent disease. However, despite in vitro evidence that certain nucleoside/nucleotide analogue reverse transcriptase inhibitors (NRTIs) are active against HTLV-1, in vivo results have been disappointing. We therefore assayed the sensitivity of HTLV-1 primary isolates to a panel of RT inhibitors. HTLV-1 primary isolates were obtained, pre- and post- NRTI treatment, from patients with HTLV-1-associated myelopathy. Sensitivity to azidothymidine (AZT), lamivudine (3TC), tenofovir (TDF) and three phosphonated carbocyclic 2’-oxa-3’aza nucleosides (PCOANs) was assessed in a RT inhibitor assay. With the exception of 3TC, HTLV RT from primary isolates was less sensitive to all tested inhibitors than HTLV-1 RT from MT-2 cells. HTLV-1 RT from primary isolates and from chronically infected, transformed MT-2 cells was insensitive to 3TC. Sensitivity of primary isolates to RT inhibitors was not reduced following up to 12 months of patient treatment with AZT plus 3TC. The sensitivity of HTLV-1 primary isolates to NRTIs differs from that of cell lines and may vary among patients. Failure of NRTIs to reduce HTLV-1 viral load in vivo was not due to the development of phenotypic NRTI resistance. AZT and the three PCOANs assayed all consistently inhibited primary isolate HTLV-1 RT. Full article

(This article belongs to the Special Issue Recent Developments in HTLV Research)

Review

Jump to: Research

1676 KiB

Open AccessReview

Human T-Lymphotropic Virus Type 1 (HTLV-1) and Regulatory T Cells in HTLV-1-Associated Neuroinflammatory Disease

by Natsumi Araya, Tomoo Sato, Naoko Yagishita, Hitoshi Ando, Atae Utsunomiya, Steven Jacobson and Yoshihisa Yamano

Viruses 2011, 3(9), 1532-1548; https://doi.org/10.3390/v3091532 - 25 Aug 2011

Cited by 46 | Viewed by 7441

Abstract

Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus that is the causative agent of adult T cell leukemia/lymphoma (ATL) and associated with multiorgan inflammatory disorders, including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and uveitis. HTLV-1-infected T cells have been hypothesized to contribute to [...] Read more.

Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus that is the causative agent of adult T cell leukemia/lymphoma (ATL) and associated with multiorgan inflammatory disorders, including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and uveitis. HTLV-1-infected T cells have been hypothesized to contribute to the development of these disorders, although the precise mechanisms are not well understood. HTLV-1 primarily infects CD4⁺ T helper (Th) cells that play a central role in adaptive immune responses. Based on their functions, patterns of cytokine secretion, and expression of specific transcription factors and chemokine receptors, Th cells that are differentiated from naïve CD4⁺ T cells are classified into four major lineages: Th1, Th2, Th17, and T regulatory (Treg) cells. The CD4⁺CD25⁺CCR4⁺ T cell population, which consists primarily of suppressive T cell subsets, such as the Treg and Th2 subsets in healthy individuals, is the predominant viral reservoir of HTLV-1 in both ATL and HAM/TSP patients. Interestingly, CD4⁺CD25⁺CCR4⁺ T cells become Th1-like cells in HAM/TSP patients, as evidenced by their overproduction of IFN-γ, suggesting that HTLV-1 may intracellularly induce T cell plasticity from Treg to IFN-γ⁺ T cells. This review examines the recent research into the association between HTLV-1 and Treg cells that has greatly enhanced understanding of the pathogenic mechanisms underlying immune dysregulation in HTLV-1-associated neuroinflammatory disease. Full article

(This article belongs to the Special Issue Recent Developments in HTLV Research)

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Open AccessReview

Cell Surface Markers in HTLV-1 Pathogenesis

by Andrea K. Kress, Ralph Grassmann and Bernhard Fleckenstein

Viruses 2011, 3(8), 1439-1459; https://doi.org/10.3390/v3081439 - 16 Aug 2011

Cited by 22 | Viewed by 5565

Abstract

The phenotype of HTLV-1-transformed CD4⁺ T lymphocytes largely depends on defined viral effector molecules such as the viral oncoprotein Tax. In this review, we exemplify the expression pattern of characteristic lineage markers, costimulatory receptors and ligands of the tumor necrosis factor superfamily, [...] Read more.

The phenotype of HTLV-1-transformed CD4⁺ T lymphocytes largely depends on defined viral effector molecules such as the viral oncoprotein Tax. In this review, we exemplify the expression pattern of characteristic lineage markers, costimulatory receptors and ligands of the tumor necrosis factor superfamily, cytokine receptors, and adhesion molecules on HTLV-1-transformed cells. These molecules may provide survival signals for the transformed cells. Expression of characteristic surface markers might therefore contribute to persistence of HTLV-1-transformed lymphocytes and to the development of HTLV-1-associated disease. Full article

(This article belongs to the Special Issue Recent Developments in HTLV Research)

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314 KiB

Open AccessReview

Converging Strategies in Expression of Human Complex Retroviruses

by Ilaria Cavallari, Francesca Rende, Donna M. D'Agostino and Vincenzo Ciminale

Viruses 2011, 3(8), 1395-1414; https://doi.org/10.3390/v3081395 - 11 Aug 2011

Cited by 17 | Viewed by 4969

Abstract

The discovery of human retroviruses in the early 1980s revealed the existence of viral-encoded non-structural genes that were not evident in previously described animal retroviruses. Based on the absence or presence of these additional genes retroviruses were classified as ‘simple’ and ‘complex’, respectively. [...] Read more.

The discovery of human retroviruses in the early 1980s revealed the existence of viral-encoded non-structural genes that were not evident in previously described animal retroviruses. Based on the absence or presence of these additional genes retroviruses were classified as ‘simple’ and ‘complex’, respectively. Expression of most of these extra genes is achieved through the generation of alternatively spliced mRNAs. The present review summarizes the genetic organization and expression strategies of human complex retroviruses and highlights the converging mechanisms controlling their life cycles. Full article

(This article belongs to the Special Issue Recent Developments in HTLV Research)

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Open AccessReview

HTLV-1 and Innate Immunity

by Chloé Journo and Renaud Mahieux

Viruses 2011, 3(8), 1374-1394; https://doi.org/10.3390/v3081374 - 8 Aug 2011

Cited by 50 | Viewed by 6453

Abstract

Innate immunity plays a critical role in the host response to a viral infection. The innate response has two main functions. First, it triggers effector mechanisms that restrict the infection. Second, it primes development of the adaptive response, which completes the elimination of [...] Read more.

Innate immunity plays a critical role in the host response to a viral infection. The innate response has two main functions. First, it triggers effector mechanisms that restrict the infection. Second, it primes development of the adaptive response, which completes the elimination of the pathogen or of infected cells. In vivo, HTLV-1 infects T lymphocytes that participate in adaptive immunity but also monocytes and dendritic cells that are major players in innate immunity. Herein, we will review the interplay between HTLV-1 and innate immunity. Particular emphasis is put on HTLV-1-induced alteration of type-I interferon (IFN-I) function. In vitro, the viral Tax protein plays a significant role in the alteration of IFN synthesis and signaling. Despite this, IFN-I/AZT treatment of Adult T‑cell Leukemia/Lymphoma (ATLL) patients leads to complete remission. We will discuss a model in which exogenous IFN-I could act both on the microenvironment of the T-cells to protect them from infection, and also on infected cells when combined with other drugs that lead to Tax down-regulation/degradation. Full article

(This article belongs to the Special Issue Recent Developments in HTLV Research)

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Open AccessReview

The Prevalence and Significance of HTLV-I/II Seroindeterminate Western Blot Patterns

by Anna Abrams, Yoshimi Akahata and Steven Jacobson

Viruses 2011, 3(8), 1320-1331; https://doi.org/10.3390/v3081320 - 2 Aug 2011

Cited by 29 | Viewed by 6371

Abstract

Human T-lymphotropic virus type I (HTLV-I) infects an estimated 15–20 million persons worldwide. A number of diseases have been associated with the virus including adult T-cell leukemia (ATL), HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP), HTLV-I uveitis, and HTLV-I-associated infective dermatitis. Once it was shown [...] Read more.

Human T-lymphotropic virus type I (HTLV-I) infects an estimated 15–20 million persons worldwide. A number of diseases have been associated with the virus including adult T-cell leukemia (ATL), HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP), HTLV-I uveitis, and HTLV-I-associated infective dermatitis. Once it was shown that there is an increased risk for developing HAM/TSP associated with blood transfusion, screening for HTLV-1 among blood banks was implemented in Japan, United States, France, and the Netherlands. This process includes detection by an enzyme immunoassay (EIA) followed by a confirmatory Western blot (WB) in which recombinant proteins specific for HTLV-I Env glycoproteins are incorporated into WB strips. HTLV-I seropositive results are defined by the presence of antibodies against either gp46 or gp62/68 (both Env protein bands) and either p19, p24, or p53 (one of the gag bands). HTLV-II seropositivity is confirmed by the presence of rgp46-II. However, numerous cases have been documented in which serum samples are reactive by EIA, but an incomplete banding pattern is displayed by subsequent confirmatory WB. Although the significance of these HTLV-I/II seroindeterminates is unclear, it may suggest a much higher incidence of exposure to HTLV-I/II than previously estimated. Full article

(This article belongs to the Special Issue Recent Developments in HTLV Research)

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306 KiB

Open AccessReview

Preventive and Therapeutic Strategies for Bovine Leukemia Virus: Lessons for HTLV

by Sabrina M. Rodríguez, Arnaud Florins, Nicolas Gillet, Alix De Brogniez, María Teresa Sánchez-Alcaraz, Mathieu Boxus, Fanny Boulanger, Gerónimo Gutiérrez, Karina Trono, Irene Alvarez, Lucas Vagnoni and Luc Willems

Viruses 2011, 3(7), 1210-1248; https://doi.org/10.3390/v3071210 - 19 Jul 2011

Cited by 152 | Viewed by 11611

Abstract

Bovine leukemia virus (BLV) is a retrovirus closely related to the human T-lymphotropic virus type 1 (HTLV-1). BLV is a major animal health problem worldwide causing important economic losses. A series of attempts were developed to reduce prevalence, chiefly by eradication of infected [...] Read more.

Bovine leukemia virus (BLV) is a retrovirus closely related to the human T-lymphotropic virus type 1 (HTLV-1). BLV is a major animal health problem worldwide causing important economic losses. A series of attempts were developed to reduce prevalence, chiefly by eradication of infected cattle, segregation of BLV-free animals and vaccination. Although having been instrumental in regions such as the EU, these strategies were unsuccessful elsewhere mainly due to economic costs, management restrictions and lack of an efficient vaccine. This review, which summarizes the different attempts previously developed to decrease seroprevalence of BLV, may be informative for management of HTLV-1 infection. We also propose a new approach based on competitive infection with virus deletants aiming at reducing proviral loads. Full article

(This article belongs to the Special Issue Recent Developments in HTLV Research)

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Open AccessReview

Molecular Determinants of Human T-lymphotropic Virus Type 1 Transmission and Spread

by Michael D. Lairmore, Rajaneesh Anupam, Nadine Bowden, Robyn Haines, Rashade A. H. Haynes II, Lee Ratner and Patrick L. Green

Viruses 2011, 3(7), 1131-1165; https://doi.org/10.3390/v3071131 - 12 Jul 2011

Cited by 36 | Viewed by 7499

Abstract

Human T-lymphotrophic virus type-1 (HTLV-1) infects approximately 15 to 20 million people worldwide, with endemic areas in Japan, the Caribbean, and Africa. The virus is spread through contact with bodily fluids containing infected cells, most often from mother to child through breast milk [...] Read more.

Human T-lymphotrophic virus type-1 (HTLV-1) infects approximately 15 to 20 million people worldwide, with endemic areas in Japan, the Caribbean, and Africa. The virus is spread through contact with bodily fluids containing infected cells, most often from mother to child through breast milk or via blood transfusion. After prolonged latency periods, approximately 3 to 5% of HTLV-1 infected individuals will develop either adult T-cell leukemia/lymphoma (ATL), or other lymphocyte-mediated disorders such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The genome of this complex retrovirus contains typical gag, pol, and env genes, but also unique nonstructural proteins encoded from the pX region. These nonstructural genes encode the Tax and Rex regulatory proteins, as well as novel proteins essential for viral spread in vivo such as, p30, p12, p13 and the antisense encoded HBZ. While progress has been made in the understanding of viral determinants of cell transformation and host immune responses, host and viral determinants of HTLV-1 transmission and spread during the early phases of infection are unclear. Improvements in the molecular tools to test these viral determinants in cellular and animal models have provided new insights into the early events of HTLV-1 infection. This review will focus on studies that test HTLV-1 determinants in context to full length infectious clones of the virus providing insights into the mechanisms of transmission and spread of HTLV-1. Full article

(This article belongs to the Special Issue Recent Developments in HTLV Research)

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Open AccessReview

HTLV-3/STLV-3 and HTLV-4 Viruses: Discovery, Epidemiology, Serology and Molecular Aspects

by Renaud Mahieux and Antoine Gessain

Viruses 2011, 3(7), 1074-1090; https://doi.org/10.3390/v3071074 - 8 Jul 2011

Cited by 64 | Viewed by 8155

Abstract

Human T cell leukemia/lymphoma virus Type 1 and 2 (HTLV-1 and HTLV-2), together with their simian counterparts (STLV-1, STLV-2), belong to the Primate T lymphotropic viruses group (PTLV). The high percentage of homologies between HTLV-1 and STLV-1 strains, led to the demonstration that [...] Read more.

Human T cell leukemia/lymphoma virus Type 1 and 2 (HTLV-1 and HTLV-2), together with their simian counterparts (STLV-1, STLV-2), belong to the Primate T lymphotropic viruses group (PTLV). The high percentage of homologies between HTLV-1 and STLV-1 strains, led to the demonstration that most HTLV-1 subtypes arose from interspecies transmission between monkeys and humans. STLV-3 viruses belong to the third PTLV type and are equally divergent from both HTLV-1 and HTLV-2. They are endemic in several monkey species that live in West, Central and East Africa. In 2005, we, and others reported the discovery of the human homolog (HTLV-3) of STLV-3 in two asymptomatic inhabitants from South Cameroon whose sera exhibited HTLV indeterminate serologies. More recently, two other cases of HTLV-3 infection in persons living in Cameroon were reported suggesting that this virus is not extremely rare in the human population living in Central Africa. Together with STLV-3, these human viral strains belong to the PTLV-3 group. A fourth HTLV type (HTLV-4) was also discovered in the same geographical area. The overall PTLV-3 and PTLV-4 genomic organization is similar to that of HTLV-1 and HTLV-2 with the exception of their long terminal repeats (LTRs) that contain only two 21 bp repeats. As in HTLV-1, HTLV-3 Tax contains a PDZ binding motif while HTLV-4 does not. An antisense transcript was also described in HTLV-3 transfected cells. PTLV-3 molecular clones are now available and will allow scientists to study the viral cycle, the tropism and the possible pathogenicity in vivo. Current studies are also aimed at determining the prevalence, distribution, and modes of transmission of these viruses, as well as their possible association with human diseases. Here we will review the characteristics of these new simian and human retroviruses, whose discovery has opened new avenues of research in the retrovirology field. Full article

(This article belongs to the Special Issue Recent Developments in HTLV Research)

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Open AccessReview

Anti-Apoptotic Effect of Tax: An NF-κB Path or a CREB Way?

by Daniela Saggioro

Viruses 2011, 3(7), 1001-1014; https://doi.org/10.3390/v3071001 - 27 Jun 2011

Cited by 15 | Viewed by 5851

Abstract

The NF-κB pathway is intimately linked to the survival of mammalian cells, and its activation by Tax has consequently been considered important for human T-cell leukemia/lymphoma virus type 1 (HTLV-1)-infected cell resistance to death. Very little emphasis has been given to other mechanisms, [...] Read more.

The NF-κB pathway is intimately linked to the survival of mammalian cells, and its activation by Tax has consequently been considered important for human T-cell leukemia/lymphoma virus type 1 (HTLV-1)-infected cell resistance to death. Very little emphasis has been given to other mechanisms, although Tax regulates the expression and activity of several cellular genes. The finding that CREB protein is activated in HTLV-1 infected cells underlines the possibility that other mechanisms of survival may be implicated in HTLV-1 infection. Indeed, CREB activation or overexpression plays a role in normal hematopoiesis, as well as in leukemia development, and CREB is considered as a survival factor in various cell systems. A better understanding of the different molecular mechanisms used by Tax to counteract cell death will also help in the development of new therapeutic strategies for HTLV-1 associated diseases. Full article

(This article belongs to the Special Issue Recent Developments in HTLV Research)

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Open AccessReview

Targeting HTLV-1 Activation of NFκB in Mouse Models and ATLL Patients

by Daniel A. Rauch and Lee Ratner

Viruses 2011, 3(6), 886-900; https://doi.org/10.3390/v3060886 - 21 Jun 2011

Cited by 21 | Viewed by 5630

Abstract

Of the millions of HTLV-1 infected carriers worldwide, 3–5% will develop an aggressive T-cell neoplasm that is highly refractory to conventional therapy. The virus carries the Tax oncogene which constitutively activates the NFκB pathway. This co-option of signaling through NFκB provides for the [...] Read more.

Of the millions of HTLV-1 infected carriers worldwide, 3–5% will develop an aggressive T-cell neoplasm that is highly refractory to conventional therapy. The virus carries the Tax oncogene which constitutively activates the NFκB pathway. This co-option of signaling through NFκB provides for the HTLV-1 infected cell an escape from cell cycle arrest and apoptosis, a steady source of growth factors, and a mechanism by which the virus can activate its own target cell. Therapies that target the NFκB pathway sensitize adult T-cell leukemia/lymphoma (ATLL) cells to apoptosis. A focus on translational interrogation of NFκB inhibitors in animal models and ATLL patients is needed to advance NFκB-targeted ATLL therapies to the bedside. Full article

(This article belongs to the Special Issue Recent Developments in HTLV Research)

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Open AccessReview

Orf-I and Orf-II-Encoded Proteins in HTLV-1 Infection and Persistence

by Dustin Edwards, Claudio Fenizia, Heather Gold, Maria Fernanda de Castro-Amarante, Cody Buchmann, Cynthia A. Pise-Masison and Genoveffa Franchini

Viruses 2011, 3(6), 861-885; https://doi.org/10.3390/v3060861 - 17 Jun 2011

Cited by 43 | Viewed by 6863

Abstract

The 3' end of the human T-cell leukemia/lymphoma virus type-1 (HTLV-1) genome contains four overlapping open reading frames (ORF) that encode regulatory proteins. Here, we review current knowledge of HTLV-1 orf-I and orf-II protein products. Singly spliced mRNA from orf-I encodes p12, which [...] Read more.

The 3' end of the human T-cell leukemia/lymphoma virus type-1 (HTLV-1) genome contains four overlapping open reading frames (ORF) that encode regulatory proteins. Here, we review current knowledge of HTLV-1 orf-I and orf-II protein products. Singly spliced mRNA from orf-I encodes p12, which can be proteolytically cleaved to generate p8, while differential splicing of mRNA from orf-II results in production of p13 and p30. These proteins have been demonstrated to modulate transcription, apoptosis, host cell activation and proliferation, virus infectivity and transmission, and host immune responses. Though these proteins are not essential for virus replication in vitro, p8, p12, p13, and p30 have an important role in the establishment and maintenance of HTLV-1 infection in vivo. Full article

(This article belongs to the Special Issue Recent Developments in HTLV Research)

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Open AccessReview

Move or Die: the Fate of the Tax Oncoprotein of HTLV-1

by Julie Lodewick, Isabelle Lamsoul and Françoise Bex

Viruses 2011, 3(6), 829-857; https://doi.org/10.3390/v3060829 - 15 Jun 2011

Cited by 21 | Viewed by 6529

Abstract

The HTLV-1 Tax protein both activates viral replication and is involved in HTLV-1-mediated transformation of T lymphocytes. The transforming properties of Tax include altering the expression of select cellular genes via activation of cellular pathways and perturbation of both cell cycle control mechanisms [...] Read more.

The HTLV-1 Tax protein both activates viral replication and is involved in HTLV-1-mediated transformation of T lymphocytes. The transforming properties of Tax include altering the expression of select cellular genes via activation of cellular pathways and perturbation of both cell cycle control mechanisms and apoptotic signals. The recent discovery that Tax undergoes a hierarchical sequence of posttranslational modifications that control its intracellular localization provides provocative insights into the mechanisms regulating Tax transcriptional and transforming activities. Full article

(This article belongs to the Special Issue Recent Developments in HTLV Research)

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Open AccessReview

Molecular Aspects of HTLV-1 Entry: Functional Domains of the HTLV-1 Surface Subunit (SU) and Their Relationships to the Entry Receptors

by Kathryn S. Jones, Sophie Lambert, Manuella Bouttier, Laurence Bénit, Frank W. Ruscetti, Olivier Hermine and Claudine Pique

Viruses 2011, 3(6), 794-810; https://doi.org/10.3390/v3060794 - 15 Jun 2011

Cited by 66 | Viewed by 7262

Abstract

The initial step in retroviral infection involves specific interactions between viral envelope proteins (Env) and specific receptors on the surface of target cells. For many years, little was known about the entry receptors for HTLV-1. During this time, however, functional domains of the [...] Read more.

The initial step in retroviral infection involves specific interactions between viral envelope proteins (Env) and specific receptors on the surface of target cells. For many years, little was known about the entry receptors for HTLV-1. During this time, however, functional domains of the HTLV-1 Env were identified by analyzing the effects of neutralizing antibodies and specific mutations in Env on HTLV-1 infectivity. More recent studies have revealed that HTLV-1 infectivity involves interactions with three different molecules: heparan sulfate proteoglycans (HSPG), the VEGF-165 receptor Neuropilin 1 (NRP-1) and glucose transporter type 1 (GLUT1). Here, we revisit previously published data on the functional domains of Env in regard to the recent knowledge acquired about this multi-receptor complex. We also discuss the similarities and differences between HTLV-1 and other deltaretroviruses in regards to receptor usage. Full article

(This article belongs to the Special Issue Recent Developments in HTLV Research)

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New Insights into HTLV-1 Particle Structure, Assembly, and Gag-Gag Interactions in Living Cells

by Keir H. Fogarty, Wei Zhang, Iwen F. Grigsby, Jolene L. Johnson, Yan Chen, Joachim D. Mueller and Louis M. Mansky

Viruses 2011, 3(6), 770-793; https://doi.org/10.3390/v3060770 - 14 Jun 2011

Cited by 22 | Viewed by 7219

Abstract

Human T-cell leukemia virus type 1 (HTLV-1) has a reputation for being extremely difficult to study in cell culture. The challenges in propagating HTLV-1 has prevented a rigorous analysis of how these viruses replicate in cells, including the detailed steps involved in virus [...] Read more.

Human T-cell leukemia virus type 1 (HTLV-1) has a reputation for being extremely difficult to study in cell culture. The challenges in propagating HTLV-1 has prevented a rigorous analysis of how these viruses replicate in cells, including the detailed steps involved in virus assembly. The details for how retrovirus particle assembly occurs are poorly understood, even for other more tractable retroviral systems. Recent studies on HTLV-1 using state-of-the-art cryo-electron microscopy and fluorescence-based biophysical approaches explored questions related to HTLV-1 particle size, Gag stoichiometry in virions, and Gag-Gag interactions in living cells. These results provided new and exciting insights into fundamental aspects of HTLV-1 particle assembly—which are distinct from those of other retroviruses, including HIV-1. The application of these and other novel biophysical approaches promise to provide exciting new insights into HTLV-1 replication. Full article

(This article belongs to the Special Issue Recent Developments in HTLV Research)

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Controversies in Targeted Therapy of Adult T Cell Leukemia/Lymphoma: ON Target or OFF Target Effects?

by Rihab Nasr, Hiba El Hajj, Youmna Kfoury, Hugues de Thé, Olivier Hermine and Ali Bazarbachi

Viruses 2011, 3(6), 750-769; https://doi.org/10.3390/v3060750 - 14 Jun 2011

Cited by 32 | Viewed by 6605

Abstract

Adult T cell leukemia/lymphoma (ATL) represents an ideal model for targeted therapy because of intrinsic chemo-resistance of ATL cells and the presence of two well identified targets: the HTLV-I retrovirus and the viral oncoprotein Tax. The combination of zidovudine (AZT) and interferon-alpha (IFN) [...] Read more.

Adult T cell leukemia/lymphoma (ATL) represents an ideal model for targeted therapy because of intrinsic chemo-resistance of ATL cells and the presence of two well identified targets: the HTLV-I retrovirus and the viral oncoprotein Tax. The combination of zidovudine (AZT) and interferon-alpha (IFN) has a dramatic impact on survival of ATL patients. Although the mechanism of action remains unclear, arguments in favor or against a direct antiviral effect will be discussed. Yet, most patients relapse and alternative therapies are mandatory. IFN and arsenic trioxide induce Tax proteolysis, synergize to induce apoptosis in ATL cells and cure Tax-driven ATL in mice through specific targeting of leukemia initiating cell activity. These results provide a biological basis for the clinical success of arsenic/IFN/AZT therapy in ATL patients and suggest that both extinction of viral replication (AZT) and Tax degradation (arsenic/IFN) are needed to cure ATL. Full article

(This article belongs to the Special Issue Recent Developments in HTLV Research)

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Human T-Cell Lymphotropic Virus: A Model of NF-κB-Associated Tumorigenesis

by Zhaoxia Qu and Gutian Xiao

Viruses 2011, 3(6), 714-749; https://doi.org/10.3390/v3060714 - 10 Jun 2011

Cited by 57 | Viewed by 6015

Abstract

Human T-cell lymphotropic virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma (ATL), whereas the highly related HTLV-2 is not associated with ATL or other cancers. In addition to ATL leukemogenesis, studies of the HTLV viruses also provide an exceptional [...] Read more.

Human T-cell lymphotropic virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma (ATL), whereas the highly related HTLV-2 is not associated with ATL or other cancers. In addition to ATL leukemogenesis, studies of the HTLV viruses also provide an exceptional model for understanding basic pathogenic mechanisms of virus-host interactions and human oncogenesis. Accumulating evidence suggests that the viral regulatory protein Tax and host inflammatory transcription factor NF-kB are largely responsible for the different pathogenic potentials of HTLV-1 and HTLV-2. Here, we discuss the molecular mechanisms of HTLV-1 oncogenic pathogenesis with a focus on the interplay between the Tax oncoprotein and NF-κB pro-oncogenic signaling. We also outline some of the most intriguing and outstanding questions in the fields of HTLV and NF-κB. Answers to those questions will greatly advance our understanding of ATL leukemogenesis and other NF-κB-associated tumorigenesis and will help us design personalized cancer therapies. Full article

(This article belongs to the Special Issue Recent Developments in HTLV Research)

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Intracellular Localization and Cellular Factors Interaction of HTLV-1 and HTLV-2 Tax Proteins: Similarities and Functional Differences

by Umberto Bertazzoni, Marco Turci, Francesca Avesani, Gianfranco Di Gennaro, Carlo Bidoia and Maria Grazia Romanelli

Viruses 2011, 3(5), 541-560; https://doi.org/10.3390/v3050541 - 9 May 2011

Cited by 32 | Viewed by 9608

Abstract

Human T-lymphotropic viruses type 1 (HTLV-1) and type 2 (HTLV-2) present very similar genomic structures but HTLV-1 is more pathogenic than HTLV-2. Is this difference due to their transactivating Tax proteins, Tax-1 and Tax-2, which are responsible for viral and cellular gene activation? [...] Read more.

Human T-lymphotropic viruses type 1 (HTLV-1) and type 2 (HTLV-2) present very similar genomic structures but HTLV-1 is more pathogenic than HTLV-2. Is this difference due to their transactivating Tax proteins, Tax-1 and Tax-2, which are responsible for viral and cellular gene activation? Do Tax-1 and Tax-2 differ in their cellular localization and in their interaction pattern with cellular factors? In this review, we summarize Tax-1 and Tax-2 structural and phenotypic properties, their interaction with factors involved in signal transduction and their localization-related behavior within the cell. Special attention will be given to the distinctions between Tax-1 and Tax-2 that likely play an important role in their transactivation activity. Full article

(This article belongs to the Special Issue Recent Developments in HTLV Research)

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Making Sense out of Antisense Transcription in Human T-Cell Lymphotropic Viruses (HTLVs)

by Benoit Barbeau and Jean-Michel Mesnard

Viruses 2011, 3(5), 456-468; https://doi.org/10.3390/v3050456 - 5 May 2011

Cited by 44 | Viewed by 6949

Abstract

Retroviral gene expression generally depends on a full-length transcript that initiates in the 5' long terminal repeat (LTR), which is either unspliced or alternatively spliced. We and others have demonstrated the existence of an antisense transcript initiating in the 3' LTR of the [...] Read more.

Retroviral gene expression generally depends on a full-length transcript that initiates in the 5' long terminal repeat (LTR), which is either unspliced or alternatively spliced. We and others have demonstrated the existence of an antisense transcript initiating in the 3' LTR of the Human T-cell Leukemia Virus type 1 (HTLV-1) that is involved in the production of HBZ (HTLV-1 basic leucine zipper (bZIP) factor). HBZ is a Fos-like factor capable of inhibiting Tax-mediated activation of the HTLV-1 LTR by interacting with the cellular transcription factor cAMP-response element-binding protein (CREB) and the pleiotropic cellular coactivators p300/CBP. HBZ can also activate cellular transcription through its interaction with p300/CBP. Interestingly, HBZ has also been found to promote T-lymphocyte proliferation. By down-regulating viral expression and by stimulating T-cell proliferation, HBZ could be essential in the establishment of a chronic infection. Antisense transcription also occurs in the closely related HTLV-2 retrovirus as well as in the recently discovered HTLV-3 and HTLV-4. These antisense transcripts are also involved in the production of retroviral proteins that we have termed Antisense Protein of HTLVs (APH). Like HBZ, the APH proteins are localized in the nucleus of transfected cells and repress Tax-mediated viral transcription. Full article

(This article belongs to the Special Issue Recent Developments in HTLV Research)

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